TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology

• Published in: Molecular cell Vol. 80; no. 5; pp. 810 - 827.e7
• Main Authors: Chen, Shasha, Liu, Shengduo, Wang, Junxian, Wu, Qirou, Wang, Ailian, Guan, Hongxin, Zhang, Qian, Zhang, Dan, Wang, Xiaojian, Song, Hai, Qin, Jun, Zou, Jian, Jiang, Zhengfan, Ouyang, Songying, Feng, Xin-Hua, Liang, Tingbo, Xu, Pinglong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.12.2020
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; antiviral immunity; cell fate determination; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - metabolism; DRP1; Dynamins - genetics; Dynamins - metabolism; HCT116 Cells; HEK293 Cells; Humans; innate immunity; Male; Mice; Mice, Transgenic; Mitochondria - physiology; mitochondrial dynamics; mitochondrion; Mutation; nucleic acid sensing; phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RLR-MAVS; RNA - genetics; RNA - metabolism; Signal Transduction - genetics; TBK1; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; nucleic acid sensing; TBK1; RLR-MAVS; antiviral immunity; innate immunity; cell fate determination; phosphorylation; mitochondrial dynamics; DRP1; mitochondrion
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.10.018

Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics. [Display omitted] •Innate immune sensing of cytosolic RNA induces profound mitochondrial fusion•The TBK1-DRP1 axis underlies RNA sensing-triggered mitochondrial reprogramming•TBK1 directly phosphorylates DRP1 to disable its multimeric assembly and function•TBK1-DRP1 signaling enables large MAVS aggregation and healthy antiviral immunity Much is still unknown about the cellular roles of innate nucleic acid sensing. Chen et al. identify an intriguing function of innate immunity in governing both morphology and physiology of a major organelle via an elegant MAVS-TBK1-DRP1 mechanism, which shapes mitochondrial dynamics to accommodate both immunity and nutrient stresses.